BACKGROUND: Papillary thyroid cancer (PTC) persistence or recurrence and the need for long-term surveillance can cause significant inconvenience and morbidity in patients. Currently, recurrence risk stratification is accomplished by using clinicopathologic factors, and serum thyroglobulin is the only commercially available marker for persistent or recurrent disease. The objective of this study was to determine microRNA (miRNA) expression in PTC and determine whether 1 or more miRNAs could be measured in plasma as a biomarker for recurrence. METHODS: Patients with recurrent PTC (Rc-PTC) and those without recurrence (NR-PTC) were retrospectively recruited for a comparison of their tumor miRNA profiles. Patients with either newly diagnosed PTC or multinodular goiter who were undergoing total thyroidectomy were prospectively recruited for an analysis of preoperative and postoperative circulating miRNA levels. Healthy volunteers were recruited as the control group. RESULTS: MicroRNA-222 and miR-146b were over-expressed 10.8-fold and 8.9-fold, respectively, in Rc-PTC tumors compared with NR-PTC tumors (P 5.014 and P 5.038, respectively). In plasma from preoperative PTC patients, levels of miR-222 and miR-146b were higher compared with the levels in plasma from healthy volunteers (P <.01 for both). Reductions of 2.7-fold and 5.1-fold were observed in the plasma levels of miR-222 and miR-146b, respectively, after total thyroidectomy (P 5.03 for both). CONCLUSIONS: This study demonstrated that tumor levels of miR-222 and miR-146b are associated with PTC recurrence and that miR-222 and miR-146b levels in the circulation correspond to the presence of PTC. The potential of these miRNAs as tumor biomarkers to improve patient stratification according to the risk of recurrence and as circulating biomarkers for PTC surveillance warrants further study. Cancer 2013;119:4358-65.

Primary aldosteronism (PA) is the most common cause of secondary hypertension with a prevalence of 5–10% in unreferred hypertensive patients. Aldosterone producing adenomas (APAs) constitute a large proportion of PA cases and represent a surgically correctable form of the disease. The WNT signaling pathway is activated in APAs. In other tumors, a frequent cause of aberrant WNT signaling is mutation in the CTNNB1 gene coding for β-catenin. Our objective was to screen for CTNNB1 mutations in a well-characterized cohort of 198 APAs. Somatic CTNNB1 mutations were detected in 5.1% of the tumors, occurring mutually exclusive from mutations in KCNJ5, ATP1A1, ATP2B3 and CACNA1D. All of the observed mutations altered serine/threonine residues in the GSK3β binding domain in exon 3. The mutations were associated with stabilized β-catenin and increased AXIN2 expression, suggesting activation of WNT signaling. By CYP11B2 mRNA expression, CYP11B2 protein expression, and direct measurement of aldosterone in tumor tissue, we confirmed the ability for aldosterone production. This report provides compelling evidence that aberrant WNT signaling caused by mutations in CTNNB1 occur in APAs. This also suggests that other mechanisms that constitutively activate the WNT pathway may be important in APA formation.

BackgroundAldosterone producing lesions are a common cause of hypertension, but genetic alterations for tumorigenesis have been unclear. Recently, either of two recurrent somatic missense mutations (G151R or L168R) was found in the potassium channel KCNJ5 gene in aldosterone producing adenomas. These mutations alter the channel selectivity filter and result in Na+ conductance and cell depolarization, stimulating aldosterone production and cell proliferation. Because a similar mutation occurs in a Mendelian form of primary aldosteronism, these mutations appear to be sufficient for cell proliferation and aldosterone production. The prevalence and spectrum of KCNJ5 mutations in different entities of adrenocortical lesions remain to be defined.Materials and MethodsThe coding region and flanking intronic segments of KCNJ5 were subjected to Sanger DNA sequencing in 351 aldosterone producing lesions, from patients with primary aldosteronism and 130 other adrenocortical lesions. The specimens had been collected from 10 different worldwide referral centers.ResultsG151R or L168R somatic mutations were identified in 47% of aldosterone producing adenomas, each with similar frequency. A previously unreported somatic mutation near the selectivity filter, E145Q, was observed twice. Somatic G151R or L168R mutations were also found in 40% of aldosterone producing adenomas associated with marked hyperplasia, but not in specimens with merely unilateral hyperplasia. Mutations were absent in 130 non-aldosterone secreting lesions. KCNJ5 mutations were overrepresented in aldosterone producing adenomas from female compared to male patients (63 vs. 24%). Males with KCNJ5 mutations were significantly younger than those without (45 vs. 54, respectively; p<0.005) and their APAs with KCNJ5 mutations were larger than those without (27.1 mm vs. 17.1 mm; p<0.005).DiscussionEither of two somatic KCNJ5 mutations are highly prevalent and specific for aldosterone producing lesions. These findings provide new insight into the pathogenesis of primary aldosteronism.